tbuckley/cabot-search huggingface dataset:
Efficacy and Safety of Once-Weekly Efpeglenatide Monotherapy Versus Placebo in Type 2 Diabetes: The AMPLITUDE-M Randomized Controlled Trial
Authors: Juan Pablo Frias, JaeDuk Choi, Julio Rosenstock, Luiza Popescu, Elisabeth Niemoeller, Isabel Muehlen-Bartmer, Seungjae Baek
Journal: Diabetes Care (2022)

To assess the efficacy and safety of the glucagon-like peptide 1 receptor agonist (GLP-1 RA) efpeglenatide versus placebo in patients with type 2 diabetes inadequately controlled with diet and exercise alone.AMPLITUDE-M was a phase 3, double-blind, placebo-controlled, multicenter trial that randomized adults with type 2 diabetes suboptimally controlled with diet and exercise alone to once-weekly efpeglenatide (2, 4, or 6 mg) or placebo for up to 56 weeks. The primary objective was to demonstrate the superiority of efpeglenatide versus placebo for HbA1c reduction at week 30. Secondary objectives included changes in other measures of glycemic control and body weight at weeks 30 and 56.At week 30, HbA1c was reduced from a baseline of 8.1% (65 mmol/mol) to 6.9% (52 mmol/mol), 6.6% (49 mmol/mol), and 6.4% (47 mmol/mol) with efpeglenatide 2, 4, and 6 mg, respectively. Least squares mean HbA1c reductions from baseline were statistically superior for each efpeglenatide dose versus placebo (2 mg, -0.5% [95% CI -0.9, -0.2; P = 0.0054]; 4 mg, -0.8% [-1.2, -0.5; P < 0.0001]; 6 mg, -1.0% [-1.4, -0.7; P < 0.0001]). A greater proportion of efpeglenatide-treated patients (all doses) achieved HbA1c <7% (53 mmol/mol) versus placebo by week 30 (P < 0.0001 for all), and significant reductions in body weight and fasting plasma glucose were also observed for efpeglenatide (4 and 6 mg doses) versus placebo at week 30 (P < 0.05 for all). Consistent with the GLP-1 RA class, gastrointestinal adverse events were most commonly reported; these were generally transient and mild/moderate in severity. Few patients reported hypoglycemia.As monotherapy in patients with type 2 diabetes, once-weekly efpeglenatide significantly improved glycemic control and body weight with a safety and tolerability profile similar to that of other GLP-1 RAs.
Rapidly adapting the clinical research environment at an NCI-designated comprehensive cancer center to the COVID-19 pandemic.
Authors: Andrew B. Lassman, Frances L. Brogan, Ryan J. Shelton, Edward Bentlyewski, Moshe A. Kelsen, Helen Kim, Brenda L. Ruotolo, Anil K. Rustgi, Joseph G. Jurcic
Journal: Journal of Clinical Oncology (2022)

e13534 Background: In March 2020, responding to COVID-19, the Columbia University Institutional Review Board (IRB) mandated all research pause in-person activities except studies “offering the potential for direct benefit” to patients. New enrollment was also paused. Columbia University Irving Medical Center concurrently mandated all non-essential employees work remotely, and all feasible patient visits transition to telehealth. The clinical research infrastructure at the Herbert Irving Comprehensive Cancer Center (HICCC) was required to adapt its operations in response. Methods: The HICCC convened an executive committee (EC), consisting of multi-disciplinary leadership, canvassed peer institutions, and engaged the IRB Executive Director (ED), Chief of Infectious Disease, a bioethicist, and others ad hoc. Results: The IRB ED agreed with the EC that all approved interventional therapeutic clinical trials for cancer (n = 554) offered the potential for direct benefit to patients. The EC established an “Emergency Preparedness” standard operating procedure (SOP) with input from the IRB and HICCC Protocol Review &amp; Monitoring and Data &amp; Safety Monitoring Committees. This SOP required assessment of each protocol for risks/benefit, transition to remote processes when possible, and referenced the Code of Federal Regulations allowing changes to a research plan without prospective IRB-approval if “necessary to eliminate apparent immediate hazard”. For new subjects, the EC created a process for enrollment as exceptions to the research pause requiring written justification by the PI that included risk-mitigation strategies and approval by the EC. 116 patients were accrued under this process. All external monitoring and auditing was transitioned to remote. Finally, 25% of research nurses and 10% of coordinators were redeployed to other short-staffed areas of the medical center. After 3 months, the IRB lifted the research pause in tranches, and the EC charged its Disease Based Teams with prioritizing trials to reopen. Accrual nadired at 30% of pre-pandemic levels in June 2020, which fully recovered by March 2021. Conclusions: A centralized research infrastructure working closely with established institutional committees was critical for the unprecedented yet effective and rapid ramp down/up of clinical trials. After 1-year, accrual recovered to pre-pandemic levels, leveraging new processes such as electronic consent, telehealth, and remote work for staff.
MRI and MRI-targeted biopsy can detect cribriform cancer of the prostate
Authors: S. Uehara, Y. Matsuoka, K. Yamamoto, Y. Nakamura, Y. Uchida, S. Fukuda, H. Tanaka, S. Yoshida, M. Yokoyama, K. Ohashi, Y. Fujii
Journal: European Urology (2022)
N-terminally truncated Aβ4-x proteoforms and their relevance for Alzheimer’s pathophysiology
Authors: Agueda Rostagno, Erwin Cabrera, Tammaryn Lashley, Jorge Ghiso
Journal: Translational Neurodegeneration (2022)

Abstract Background The molecular heterogeneity of Alzheimer’s amyloid-β (Aβ) deposits extends well beyond the classic Aβ1-40/Aβ1-42 dichotomy, substantially expanded by multiple post-translational modifications that increase the proteome diversity. Numerous truncated fragments consistently populate the brain Aβ peptidome, and their homeostatic regulation and potential contribution to disease pathogenesis are largely unknown. Aβ4-x peptides have been reported as major components of plaque cores and the limited studies available indicate their relative abundance in Alzheimer’s disease (AD). Methods Immunohistochemistry was used to assess the topographic distribution of Aβ4-x species in well-characterized AD cases using custom-generated monoclonal antibody 18H6—specific for Aβ4-x species and blind for full-length Aβ1-40/Aβ1-42—in conjunction with thioflavin-S and antibodies recognizing Aβx-40 and Aβx-42 proteoforms. Circular dichroism, thioflavin-T binding, and electron microscopy evaluated the biophysical and aggregation/oligomerization properties of full-length and truncated synthetic homologues, whereas stereotaxic intracerebral injections of monomeric and oligomeric radiolabeled homologues in wild-type mice were used to evaluate their brain clearance characteristics. Results All types of amyloid deposits contained the probed Aβ epitopes, albeit expressed in different proportions. Aβ4-x species showed preferential localization within thioflavin-S-positive cerebral amyloid angiopathy and cored plaques, strongly suggesting poor clearance characteristics and consistent with the reduced solubility and enhanced oligomerization of their synthetic homologues. In vivo clearance studies demonstrated a fast brain efflux of N-terminally truncated and full-length monomeric forms whereas their oligomeric counterparts—particularly of Aβ4-40 and Aβ4-42—consistently exhibited enhanced brain retention. Conclusions The persistence of aggregation-prone Aβ4-x proteoforms likely contributes to the process of amyloid formation, self-perpetuating the amyloidogenic loop and exacerbating amyloid-mediated pathogenic pathways.
The ratio of PD1+CD8+T cells in stromal area of tumor tissue is associated with the effect of neoadjuvant chemotherapy in HER2 negative breast cancer patients.
Authors: Chang Gong, Qun Lin, Yinghuan Cen, Xiaolin Fang, Yu Shi, Letian Chen, Qing Luo, Zhuxi Duan
Journal: Journal of Clinical Oncology (2022)

e12626 Background: For patients diagnosed with early breast cancer, surgery remains the standard of care. Early patients achieving pathological complete response (pCR) after neoadjuvant therapy have been proved to be associated with improved survival. However, the accurate prediction of pCR in a clinical setting remains challenging. Tumor infiltrating lymphocyte (TIL) levels have recently been identified as an independent predictor of pCR in breast cancer. However, due to extremely complex tumor microenvironment within tumor, the role of different immune cell subtypes in neoadjuvant chemotherapy (NAC) is inconclusive. This study aimed to explore the potentially predictive role and dynamic changes of immune cell subsets in patients with HER2 negative breast cancer receiving NAC. Methods: Since January 2020, tumor tissue samples of 12 HER2 negative breast cancer patients were collected at baseline and after NAC. Several kinds of immune cells including CD3+T cells, CD4+T cells, CD8+T cells, PD-1+CD8+T cells, Tregs, M1/M2 tumor associated macrophages(TAM), PD-L1+CD68+TAM, B cells, CD56bright NK cells and CD56dim NK cells in the tumor tissue were evaluated by multiple fluorescence immunohistochemistry (mIHC) and counted in intratumoral and stromal area for density and ratio. T test was used for the comparison of immune cells and statistical significance was set at p = 0.05. Results: We examined immune cell subtypes and PD-L1/PD-1 expression of 12 HER2 negative breast cancer patients. According to achieving pCR or not, these 12 patients were divided into two groups, pCR (n = 3) and non-pCR group (n = 9). The results showed that the ratio of PD1+CD8+T cells in stromal area of baseline tumor tissue of pCR group was significantly higher than non-pCR group (median ratio, pCR group vs. non-pCR group = 17.3% vs. 3.6%, p = 0.029).In addition, the ratio of PD1+CD8+T cells in stromal area of pCR group was still significantly higher than that of non pCR patients after NAC (median ratio, pCR group vs. non-pCR group = 20.7% vs. 2.6%, p = 0.0003). Conclusions: Whether at baseline or after NAC, the ratio of PD1+CD8+T cells in stromal area is associated with the effect of NAC in HER2 negative breast cancer.
LGG-06. Selumetinib in pediatric patients with non-neurofibromatosis type 1-associated, non-optic pathway (OPG) and non-pilocytic recurrent/progressive low-grade glioma harboring BRAFV600E mutation or BRAF-KIAA1549 fusion: a multicenter prospective Pediatric Brain Tumor Consortium (PBTC) Phase 2 trial
Authors: Jason Fangusaro, Arzu Onar-Thomas, Tina Young Poussaint, Shelly Lensing, Shengjie Wu, Azra H Ligon, Neal Lindeman, Clinton F Stewart, David T W Jones, Stefan M Pfister, Natasha Pillay Smiley, James Leach, Roger Packer, Gilbert Vezina, Alicia Lenzen, Alok Jaju, Stewart Goldman, Laurence Austin Doyle, Malcolm Smith, Maryam Fouladi, Ira Dunkel
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: A greater understanding of the Ras-MAP kinase pathway in pediatric low-grade glioma (LGG) paired with the availability of selective inhibitors has enhanced the ability to target this pathway with therapeutic intent. METHODS: The PBTC conducted a multi-institutional phase II study (NCT01089101) evaluating selumetinib (AZD6244, ARRY-142886), a MEK I/II inhibitor, in children with recurrent/progressive LGG assigned to 6 strata and treated at a dose of 25 mg/m2/dose PO BID for up to two years. Here we present stratum 5 which enrolled children without NF1, non-OPG and non-pilocytic LGG harboring either a BRAFV600E mutation or BRAF-KIAA1549 fusion. RESULTS: Twenty-four of 25 children enrolled were eligible; 23 were evaluable for the primary radiologic response endpoint. Enrollment stopped early due to slow accrual and initiation of COG ACNS1931. The most common histologies were ganglioglioma (42%) and astrocytoma NOS (33%). Thirteen tumors (54%) had BRAF-KIAA1549 fusion; 11 (46%) had the BRAFV600E mutation. Five of 23 (22%) evaluable patients achieved a centrally confirmed partial response (PR), 12 (52%) had stable disease and 6 (26%) had progression with a 2-year progression-free survival of 75 + 9%. Four of 11 (36%) patients with a BRAFV600E mutation and 1/12 (8%) with a BRAF-KIAA1549 fusion achieved a PR. The 2-year PFS did not significantly differ between tumors with BRAFV600E mutation (82 + 12%) versus BRAF-KIAA1549 fusion (68 + 13%) (n=24, p=0.548). No patient remains on therapy. The most common attributable toxicities were grade 1/2 ALT/AST elevation, dry skin and leukopenia. Rare grade 3/4 toxicities included elevated CPK, rash, paronychia, fever, weight gain and sinus tachycardia. CONCLUSIONS: Despite lower than planned accrual, selumetinib met the design threshold for success in treating children with recurrent/progressive non-pilocytic, non-OPG LGG without NF1 that harbored the common BRAF aberrations. Ongoing phase 3 prospective studies will better determine the role of this agent in this population.
DIPG-47. TSO500ctDNA sequencing reveals oncogenic mutations and copy number variations in the liquid biome of children with diffuse midline glioma
Authors: Erin R Bonner, Robin Harrington, Augustine Eze, Miriam Bornhorst, Cassie N Kline, Adam Dawood, Biswajit Das, Li Chen, Rini Pauly, P Mickey Williams, Chris Karlovich, Amanda Peach, D'Andra Howell, James Doroshow, Lindsay Kilburn, Roger J Packer, Sabine Mueller, Javad Nazarian
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Molecular profiling of childhood CNS tumors is critical for diagnosis and clinical management, yet tissue access is restricted due to sensitive neuroanatomical locations. Moreover, CNS tumors including diffuse midline glioma (DMG) exhibit mutational heterogeneity and clonal evolution, which cannot be captured by upfront diagnostic biopsy alone. To address the lack of tumor visibility, and tprovide opportunity for longitudinal sampling, we validated and optimized a commercially available deep sequencing platform for analysis of circulating tumor DNA (TSO500ctDNATM). METHODS: In a proof-of-concept study, we defined the sensitivity, specificity, and clinical relevance of our novel ctDNA platform via analysis of paired tissue, CSF, and blood from children with DMG (n=10). Paired samples were assessed for concordance and sequencing results were compared to digital droplet PCR (ddPCR) detection of prognostic H3K27M mutation. RESULTS: DMG associated mutations in genes including H3-3A, H3C2, TP53, and ACVR1 were detected in ctDNA, including in CSF samples with low (&amp;lt;5ng) starting DNA input. Of 9 H3K27M mutations identified in tumor, 8 were present in CSF and 3 in plasma/serum, for a positive percent agreement with tumor results of 89% and 33%, respectively. Among CSF samples, H3.3K27M was detected in 6/6 cases, and H3.1K27M in 2/3 cases, with variant allele frequencies comparable to ddPCR results. CNVs including PDGFRA, KIT, and MDM4 gains were detected in CSF and paired tumor. Low frequency events including ACVR1, PIK3CA activating mutations and KRAS amplification were detected in CSF but absent from paired tumor, indicating tissue heterogeneity. Strategies to optimize ctDNA detection, including optimization of ctDNA isolation and adjustment of library QC metrics, were identified. CONCLUSION: Targeted ctDNA deep sequencing is feasible, can inform on clinically relevant tumor mutation and CNV profiling, and provides an opportunity for longitudinal monitoring of tumor genomic evolution in the liquid biome of children with CNS tumors.
Impact of the time elapsed between prostate biopsy and surgery on the accuracy of the Briganti nomogram predicting lymph node invasion in men with clinically localized prostate cancer
Authors: G. Gandaglia, E. Mazzone, E. Zaffuto, G. Sorce, F. Pellegrino, L. Nocera, A. Stabile, U. Capitanio, A. Larcher, F. Dehò, A. Salonia, P.I. Karakiewicz, S. Shariat, F. Montorsi, A. Briganti
Journal: European Urology (2022)
SWK-03. Neuroimaging in CNS tumours: To GA , or not to GA, that is the question.
Authors: Jade Ryles, Lisa Ternent, Gail Halliday, Rebecca M Hill, Simon Bailey
Journal: Neuro-Oncology (2022)

Abstract Children with a Central Nervous System (CNS) tumour have frequent magnetic resonance imaging (MRI) scans during their disease trajectory. Younger children routinely have these performed under general anaesthetic (GA) with an associated risk and inconvenience. Our project over a two-year period was to introduce a structured programme to any child over the age of five years old to achieve an MRI scan without the need for a GA. Thirty-six patients took part. The motivation behind this project was to enhance the hospital experience for patients and their families, lessen time spent in hospital and minimise risk. In addition, there was an added incentive of cost saving and increased availability of GA scans for other specialities within the hospital setting. During the COVID pandemic, it has also resulted in a reduction of our patients requiring COVID swabs, and isolation and in turn a reduction in aerosol generating procedures. As part of the structured programme, each child had an initial assessment with the nurse specialist followed by a minimum of one play preparation session with the play specialist. Children were required to demonstrate they could follow simple instructions, engage in social stories and role-play with hospital equipment and specialised resources. During these sessions, the children visited the MRI department where they practiced lying flat on the MRI bed as it moved into the scanner. Over the two-year period, of the total number of MRI scans performed, the amount of MRI scans requiring a GA reduced from 41% to 31%. The quality of the MRI scans was scrutinised and shown not to be significantly affected. In summary, by introducing a structured programme, it is possible to significantly reduce the need for GA in children requiring CNS imaging as part of their tumour journey.
Managing cardiotoxicity in metastatic non-small cell lung cancer (NSCLC) patients treated with tyrosine kinase inhibitors (TKIs).
Authors: Nabil Sukar, Damaal Walker, Katerine Dumais, Hermán Wesley Powery, Luis E. Raez, Pyi Phyo Aung
Journal: Journal of Clinical Oncology (2022)

e21072 Background: Current guidelines for prevention and monitoring cardiac dysfunction in patients with cancer state there is insufficient evidence to support surveillance strategies for TKIs alone. Furthermore, risk stratification for baseline and frequency of monitoring remains unclear for various products. This study evaluates the current practice for screening and monitoring for cardiotoxicity in patients treated for NSCLC with TKIs and the adherence rate to the standards of care. Methods: A single-center retrospective chart review of 113 patients with metastatic NSCLC who received TKIs at a large academic-community cancer center was performed. The current practice for screening and monitoring for cardiotoxicity and the adherence rate to the suggested standards recommended by the prescribing information of each drug were analyzed. Total incidence of cardiotoxicity was also evaluated. Descriptive statistics were calculated for all demographic variables and clinical outcome endpoints. Incidence of cardiotoxic adverse events were reported as percentages. Results: A total of 113 metastatic NSCLC patients were identified with the majority of patients taking osimertinib (67.3%), alectinib (8.0%), or dabrafenib/trametinib (7.1%) at baseline. Total adherence rate for screening and monitoring for cardiotoxicity as recommended by the prescribing information for all agents was 54%. Cardiotoxicity occurred in 46 (40.7%) patients, presenting most frequently as hypertension and bradycardia. Cohort cardiotoxicity events are summarized in the table below. Decreased left ventricular ejection fraction (LVEF) ≥ 10% or to &lt; 50% occurred in 6/76 (7.9%) patients on osimertinib; however, only 12 (15.8%) patients were able to be assessed due to lack of baseline data. Osimertinib was held and/or discontinued in 3 (3.9%) patients and 1 (1.3%) death resulted due to cardiomyopathy. QTc interval prolongation occurred in 2 (33.3%) patients on afatinib, 1 (20%) patient on crizotinib, and 1 (1.3%) patient on osimertinib. Three (3.9%) patients on osimertinib were diagnosed with atrial fibrillation. Conclusions: The results reported in this study show higher rates of decreased LVEF and similar rates of QTc prolongation with osimertinib compared to prior studies. The increased rate of hypertension observed may be associated with the high rate of uncontrolled blood pressure at baseline. Low adherence rates to the recommendations provided by prescribing information may contribute to increased risk of cardiac dysfunction.[Table: see text]
NFB-12. Effect of trametinib on leg length discrepancy in a child with NF1 related plexiform neurofibroma
Authors: Celia Pradeep, Marcel Abouassaly, Zarina Assis, Melanie Finkbeiner, Lucie Lafay-Cousin
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Plexiform neurofibroma(PN) is a challenging benign tumor. Recently, MEK inhibitors (MEKi) showed encouraging tumor response. We report the observed effect of Trametinib on leg length discrepancy (LLD) in a child with NF1. CASE DESCRIPTION: A 4 year old girl with sporadic NF1, developed progressive bilateral L1-L5 paraspinal PN extending to the left thigh resulting in hypertrophy of left leg and associated with LLD. At 33 months of age, length difference of 2.8 cm between both femurs was described on scanogram with a projected LLD of at 6.1- 6.2 cm LLD at bone maturity using the multiplier method, a common method of predicting LLD. At 36 months of age, treatment with Trametinib was initiated for her large PN. Ten months into therapy, parents reported impression of decrease swelling of her left thigh enlargement. MRI evaluation showed stable measurement of PN using the RECIST criteria. Repeat measurement on scanogram at 46 months of age disclosed a stable difference of 2.8 cm between both femurs, with a LLD projected at 5.2-5.3 cm at maturity by multiplier method. Bone age at study entry and at 11 months into therapy (Greulich-Pyle) was reported normal for chronologic age. DISCUSSION/CONCLUSION: LLD has not been commonly described in association with NF1 related PN. Given the PN involved mainly the left thigh in our patient, it is reasonable to suggest common underlying mechanism for the PN and faster growth of her left femur. Although with limited time point’s measurements, the early observation of stabilization of the LLD, 10 months into Trametinib therapy suggesting a final discrepancy in femurs length less than initially predicted, is encouraging. Further evaluation at completion of treatment and on follow-up are needed. Larger case series will be useful to explore this unexpected and possible clinical effect of MEKi in NF1 children.